Regulation of plasminogen activator inhibitor 1 expression by interaction of epidermal growth factor with progestin during decidualization of human endometrial stromal cells.

OBJECTIVE: During human pregnancy implantation, trophoblasts invade maternal blood vessels in a process that risks hemorrhage. Previous studies have demonstrated enhanced expression of type 1 plasminogen activator inhibitor, the primary inhibitor of fibrinolysis, during progestin-induced decidualization of estradiol-primed human endometrial stromal cells in vivo and in vitro. Decidual cell-expressed plasminogen activator inhibitor 1 is appropriately positioned to avert implantational hemorrhage. Because of the absence of estrogen or progesterone response elements from the plasminogen activator inhibitor 1 gene promoter, I posited that epidermal growth factor mediates these steroid effects and that expression of epidermal growth factor receptor in human endometrial stromal cells is under ovarian steroid control. STUDY
DESIGN: Confluent human endometrial stromal cells were exposed to vehicle control or to either estradiol (10(-8) mol/L) or medroxyprogesterone acetate (10(-7) mol/L), or both, with or without growth factors. After 40 hours the cultures were analyzed for plasminogen activator inhibitor 1 protein and messenger ribonucleic acid expressions. Immunostaining for epidermal growth factor receptor was carried out in sections of cycling and gestational endometrial tissues.
RESULTS: In the absence of steroids, epidermal growth factor did not alter plasminogen activator inhibitor 1 expression. In the absence of epidermal growth factor, estradiol and medroxyprogesterone acetate enhanced human endometrial stromal cell-secreted plasminogen activator inhibitor 1 protein levels 8-fold (n = 12; P <.001), whereas estradiol alone had no effect. Marked synergistic increases in plasminogen activator inhibitor 1 levels were elicited when epidermal growth factor was added with estradiol and medroxyprogesterone acetate (n = 12; 65-fold; P <.0001). Both transforming growth factor alpha and epidermal growth factor, which act through epidermal growth factor receptor, increased steady-state plasminogen activator inhibitor 1 messenger ribonucleic acid levels several-fold when added with estradiol and medroxyprogesterone acetate. In contrast, transforming growth factor beta, which does not activate epidermal growth factor receptor, did not elevate plasminogen activator inhibitor 1 messenger ribonucleic acid or protein levels whether added alone or with estradiol and medroxyprogesterone acetate. In correspondence with these in vitro observations, immunostaining for epidermal growth factor receptor was increased in human endometrial stromal cells undergoing decidualization in sections of secretory phase and first-trimester endometrial tissue.
CONCLUSIONS: Taken together, these in vitro and in vivo results indicate that both epidermal growth factor and progesterone receptors are required for maximal plasminogen activator inhibitor 1 expression by human endometrial stromal cells.